Background: Disability resulting from stroke and traumatic brain injury represent the main causes of long-term complications in adults. There are no universally accepted treatments available to treat these conditions and the financial, personal, familial and social cost of these disabilities cannot be underestimated. Preliminary data from different laboratories have shown that it is possible to modulate plastic processes in the lesioned brain via pharmacological, or brain and somatosensory stimulation techniques. The purpose of this project is to identify mechanisms of stroke motor disability and characterize the most promising techniques to improve cortical plasticity in these patients to enhance functional recovery. Findings this year: Traumatic brain injury (TBI) is a major cause of adult disability in the U.S. and worldwide, typically resulting in disruption of heterogeneous set of human motor and cognitive abilities severely impacting activities of daily living. The ability to focus ones attention on complex tasks and inhibit undesirable actions or filter out irrelevant information (i.e. inhibitory control) is one of these essential cognitive skills. We investigated the impact of mild TBI on inhibitory control in a group of seventeen patients compared to an additional seventeen age-matched healthy adults. Inhibitory control in both groups was assessed using a variant of the Stroop task and an attention-demanding 4-choice response task (4CRT). The 4CRT task utilized identical stimuli presented within two different contexts: (1) only routine responses were required and (2) routine responses were occasionally interspersed with response conflicts. For the 4CRT task, we found that mild TBI patients performed equally well as the age-matched healthy adults for the routine response context. However, within the context where occasional response conflicts were introduced, mild TBI patients who had previously experienced even a single concussion event displayed a significant increase in response time as well as higher error rates relative to healthy adults. Event-related functional magnetic resonance imaging (fMRI) results displayed corresponding changes in brain activity patterns localized to cerebello-thalamo-cortical and fronto-basal-ganglia networks known to regulate inhibitory control. These results suggest that although mild TBI patients on average display normal behavioral responses within the context of routine tasks or daily living activities, they may experience long-lasting deficits in situations requiring appropriate alternation of responses in the presence of unexpected conflicts. Over the past year, we were also able to advance several initiatives related to stroke research. MRI is an important tool used for acute diagnoses and for tracking the progression of brain lesions following stroke. However, current analytical methods used to evaluate blood perfusion deficiencies measured with MRI following stroke (e.g. - time-to-peak TTP or mean-transit time MTT) are prone to model-selection biases which can result in inaccurate estimates. We developed a novel and robust model-free approach to temporal similarity perfusion (TSP) mapping and compared its ability and reliability to detect perfusion deficits relative to traditional methods in a sample of forty patients experiencing acute ischemia via stroke or a transient ischemic attack. Two neuroradiologists (blinded to analytical method) used real-time interactive maps and summary TSP maps generated using our proposed method and traditional TTP/MTT maps to determine regions blood perfusion deficiencies within the brain. Lesion volumes identified using each methods were compared for volumetric inter-rater reliability, spatial concordance between perfusion deficits and healthy tissue and contrast-to-noise ratio (CNR). We found that blood perfusion deficiencies were correctly identified in all patients with acute ischemia. Out novel TSP map method displayed higher inter-rater reliability compared to the traditional TTP/MTT maps. Furthermore, while there was a high similarity between the lesion volumes depicted by both the TSP and TTP/MTT methods (Pearson's correlation r(18) = 0.73, p<0.0003)), our novel TSP method displayed a greater effective CNR compared to the TTP (352.3 vs 283.5, t(19) = 2.6, p<0.03.) and MTT (228.3, t(19) = 2.8, p<0.03) approaches. In summary, TSP maps appear to be a reliable and robust model-free method for accurate detection of perfusion deficiencies and lesion volume delineation compared to traditional methods. This approach has the added bonus of being computationally faster and more easily automated than traditional approaches as well, which has the potential to improve the speed and accuracy acute stroke diagnoses and decision-making for clinical trial inclusion and treatment plans. Over the past year, we continued a series of successful contributions with both domestic and international research institutions. In collaboration with Dr. Adrian Guggisberg at the University of Geneva, we previously published a project that used Fugl-Meyer Assessment (FMA) scores and diffusion-weighted MRI (dw-MRI) measures of corticospinal tract degeneration in the first few days following stroke to predict longitudinal motor recovery patterns (Buch et al., 2016). More recently, we extended this finding in two important ways. First, we replicated our previously reported results in an independent sample of 63 patients. Second, in this sample we performed a longitudinal and multimodal assessment of functional and structural changes in brain organization associated with improved recovery outcomes. Fugl-Meyer Assessments of the upper extremity were used to evaluate motor function, and high-density electroencephalography (EEG) and dw-MRI were used to assess longitudinal functional and structural changes in brain brain organization, respectively, at between 2 and 4 weeks (T0) and at 3 months (T1) after stroke onset. We found that greater integrity of the corticospinal tract (CST) and greater EEG functional connectivity (FC) between the affected hemisphere and rest of the brain, in particular between the ventral premotor and the primary motor cortex was a strong predictor of greater motor recovery following stroke. Furthermore, patients experiencing poor longitudinal motor recovery displayed unique degradation patterns of corticocortical and corticofugal fiber tracts in the affected hemisphere between T0 and T1. In summary, these findings suggest that links between initial CST integrity, systems-level cortical network plasticity, and reduction of white matter atrophy are important factors for clinical motor recovery after stroke, and identifies these factors as candidate treatment targets. In collaboration with Dr. Janine Reis at the University of Freiburg and Dr. Heidi Schambra at NYU, we investigated the effects of transcranial direct current stimulation (tDCS) on different stages of motor learning, as well as generalization of these effects to untrained motor skills. In a randomized, double-blind study of 56 mildly impaired chronic stroke patients, tDCS was applied to the ipsilesional primary motor cortex during 5 days of training on a difficult fine motor skill task to which all participants were nave. Both online and offline learning were assessed during training and retention was measured at multiple time-points over the subsequent 4-month period. We also assessed generalization of overall learning to untrained tasks. Patients receiving tDCS (real tDCS group) displayed improved motor learning relative to the sham tDCS group, with most of these gains explained by differences between the groups during the online stage. Effects of training, but not tDCS, were observed for long-term retention and for generalization of learning to untrained tasks. In summary, whi